PROJECT SUMMARY Neovascular age-related macular degeneration (AMD), characterized by the presence of choroidal neovascularization (CNV), accounts for the majority of AMD related vision loss. Invasive dye-based fluorescein angiography (FA) remains the gold standard for CNV detection. Using high-speed OCT systems, we have developed novel OCT angiography (OCTA) technologies to image CNV as well as vascular plexuses associated with AMD. Our recent clinical studies have demonstrated that (1) 33-mm OCTA has a sensitivity for subfoveal CNV detection comparable to FA; (2) OCTA derived quantitative metrics provide novel insight into the CNV response to anti-VEGF treatment; and (3) routine screening OCTA can detect treatment nave non-exudative CNV that carries high risk for progression and is invisible with FA. Currently, OCTA is limited by low transverse resolution, small field of view, and various artifacts. The current proposal will overcome these limitations by improving both the hardware platform and software algorithms to develop advanced OCTA. Its role in AMD evaluation and management will be tested in three clinical studies. 1. Develop high-resolution wide-field OCTA. We will develop a swept-source OCT prototype that is 4 times faster than current commercial OCT systems. A wide collimated beam will be used to improve transverse optical resolution. The high-speed and high-resolution OCTA will be able to image capillary-level details in a wide field of view. 2. Develop volumetric analysis of CNV and plexus-specific analysis of retinal and choroidal circulations. We will improve our algorithm to remove projection artifacts in the outer retina that arise from moving blood cells in superficial retinal vessels. Next, we will develop automated software to measure CNV volume and to detect defects in the choriocapillaris and retinal deep capillary plexus (DCP). 3. Evaluate advanced OCTA for AMD in clinical studies. Three studies will test the clinical applications of OCTA. Study 1: A cross-sectional analysis will compare the accuracy of OCTA versus FA to distinguish CNV as the etiology of macular edema versus control eyes with macular edema from retinal vein occlusion or diabetic retinopathy. Study 2: A longitudinal analysis of neovascular AMD under a treat-and-extend anti- VEGF regimen will determine if OCTA can predict recurrent exudation or hemorrhage. Study 3: An OCTA longitudinal screening of eyes with intermediate AMD will determine if choriocapillaris and retinal DCP defects presage CNV development. Non-exudative CNV detected with OCTA will be followed monthly and novel CNV volumetric analysis used to determine if rapid growth is a risk for development of exudation. If successful, OCTA will improve our capability to diagnose all macular CNVs, provide useful information to help determine appropriate anti-VEGF dosing intervals, and aid with surveillance of eyes at risk for development of neovascular AMD. OCTA is nearing its potential to replace the need for invasive FA.